Discovery
Syncoilin is a muscle-specific atypical
type III intermediate filament protein encoded in the human by the gene ''SYNC''.
It was first isolated as a binding partner to
α-dystrobrevin, as determined by a
yeast two-hybrid
Two-hybrid screening (originally known as yeast two-hybrid system or Y2H) is a molecular biology technique used to discover protein–protein interactions (PPIs) and protein–DNA interactions by testing for physical interactions (such as bindi ...
assay.
Later, a yeast two-hybrid method was used to demonstrate that syncoilin is a binding partner of
desmin
Desmin is a protein that in humans is encoded by the ''DES'' gene. Desmin is a muscle-specific, type III intermediate filament that integrates the sarcolemma, Z disk, and nuclear membrane in sarcomeres and regulates sarcomere architecture.
Str ...
.
These binding partners suggest that syncoilin acts as a mechanical "linker" between the
sarcomere
A sarcomere (Greek σάρξ ''sarx'' "flesh", μέρος ''meros'' "part") is the smallest functional unit of striated muscle tissue. It is the repeating unit between two Z-lines. Skeletal muscles are composed of tubular muscle cells (called musc ...
Z-disk (where desmin is localized) and the
dystrophin
Dystrophin is a rod-shaped cytoplasmic protein, and a vital part of a protein complex that connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix through the cell membrane. This complex is variously known as the costa ...
-associated protein complex (where α-dystrobrevin is localized). However, the specific ''in vivo'' functions of syncoilin have not yet been determined.
Through the use of Western blotting techniques, a second species of syncoilin was found. This species was 55kDa in size, whereas the original species of syncoilin was 64kDa in size. This discovery inspired scientists to use gene splicing to identify two new isoforms called SYNC2 and SYNC3.
Abnormally high levels of syncoilin have been shown to be a characteristic of neuromuscular wasting diseases such as desminopathy
and
muscular dystrophy
Muscular dystrophies (MD) are a genetically and clinically heterogeneous group of rare neuromuscular diseases that cause progressive weakness and breakdown of skeletal muscles over time. The disorders differ as to which muscles are primarily affe ...
.
Therefore, syncoilin is being explored as a promising marker of neuromuscular disease.
Structure
Syncoilin is characterized as an intermediate filament and contains the key structural features that make up intermediate filaments such as a head region, linker regions, alpha helices, and a tail region. Each protein that is classified as an intermediate filament will vary in the size and shape of their head and tail regions.
More specifically, syncoilin is structurally defined by its central rod domain that forms a coil made up of 4 subunits, an α-helical region separated by flexible linkers, a N-terminal head domain, and a C-terminal tail domain.
The isoform of syncoilin, SYNC 3, has a much different structure than the original protein filament. This isoform has a truncated rod domain and lacks a C-terminal tail region.
Because the tail of syncoilin is so short, it is hypothesized that this affects the ability of syncoilin to form other filaments.
Syncoilin is different from other type III intermediate filaments because it has a unique N-terminal that is unlike any other protein. Syncoilin does not have the capability of forming dimers spontaneously like other filaments.
Function
The most important job of syncoilin is to provide linkage between DAPC proteins and α-dystrobrevin. Studies have yet to determine if the binding of synacoilin to DAPC proteins and α-dystrobrevin occurs simultaneously.
Syncoilin, like other intermediate filaments, is also necessary for the supporting the structure of the muscle fiber.
However, syncoilin does not serve the same function as most other intermediate filaments. It can be used in an attempt to fix muscle that has been damaged through
up-regulation
In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary pro ...
.
Studies have shown that the upregulation of syncoilin is not just harmful to muscle fibers. Upregulation has also been proven to help with muscle membrane stability.
Hepatic stellate cell
Hepatic stellate cells (HSC), also known as perisinusoidal cells or Ito cells (earlier ''lipocytes'' or ''fat-storing cells''), are pericytes found in the perisinusoidal space of the liver, also known as the space of Disse (a small area between th ...
s are a specialized tissue type in the body that require syncoilin intermediate filaments. When an injury occurs to the liver, expression of intermediate filaments such as syncoilin and an increase in α-smooth muscle cells (α-SMA). It is now used to help mark activated hepatic stellate cells after being identified in an experiment done on primary liver cells in mice. In this study, syncoilin isoforms SYNC1 and SYNC2 were highly expressed during in vivo activation of hepatic stellate cells.
Location
Syncoilin is found in skeletal and cardiac muscle which is similar to its binding protein desmin.
The region of skeletal muscle that houses most of the syncoilin is the
sarcolemma
The sarcolemma (''sarco'' (from ''sarx'') from Greek; flesh, and ''lemma'' from Greek; sheath) also called the myolemma, is the cell membrane surrounding a skeletal muscle fiber or a cardiomyocyte.
It consists of a lipid bilayer and a thin oute ...
.
If the muscle tissue is dissected further into individual muscle fibers, it can be found on
neuromuscular junction
A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron and a muscle fiber.
It allows the motor neuron to transmit a signal to the muscle fiber, causing muscle contraction.
Muscles require innervation to ...
s. Syncoilin is also enriched in areas such as the perinuclear space and myotendinous junction. When there is a lack of either α-dystrobrevin or desmin, the expression of syncoilin is changed in order to compensate for the loss of one or both of the proteins.
In addition to another intermediate filament called
peripherin
Peripherin is a type III intermediate filament protein expressed mainly in neurons of the peripheral nervous system. It is also found in neurons of the central nervous system that have projections toward peripheral structures, such as spinal motor ...
, syncoilin can also be found in the
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
and the
peripheral nervous system
The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brain ...
. The spinal cord is able to express variants of the original SYNC gene into two alternate
isoforms
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...
called SYNC1 and SYNC2. However, SYNC1 and SYNC2 are dominant in different nervous systems. SYNC1 is more typically found in the brain and SYNC2 is typically found in the peripheral nervous system and spinal cord.
Clinical significance
Muscular diseases
When skeletal and cardiac muscle contain increased levels of syncoilin, it can often lead to disease in the muscle tissue.
Examples of diseases that syncoilin has been linked to include:
*
Duchenne muscular dystrophy
Duchenne muscular dystrophy (DMD) is a severe type of muscular dystrophy that primarily affects boys. Muscle weakness usually begins around the age of four, and worsens quickly. Muscle loss typically occurs first in the thighs and pelvis fol ...
*
Becker muscular dystrophy
Becker muscular dystrophy is an X-linked recessive inherited disorder characterized by slowly progressing muscle weakness of the legs and pelvis. It is a type of dystrophinopathy. This is caused by mutations in the dystrophin gene, which encodes ...
*
Central core disease
Central core disease (CCD), also known as central core myopathy, is an autosomal dominantly inherited muscle disorder present from birth that negatively affects the skeletal muscles. It was first described by Shy and Magee in 1956. It is charact ...
*
Congenital muscular dystrophies
Congenital muscular dystrophies are autosomal recessively-inherited muscle diseases. They are a group of heterogeneous disorders characterized by muscle weakness which is present at birth and the different changes on muscle biopsy that ranges fr ...
* Neurogenic disorder
Syncoilin strongly interacts with the filament, desmin, which suggests that a mutation in syncoilin might affect the bond between desmin and the sarcolemma. This may result in
desmin-related myopathy.
Another cause of muscular diseases is a mutation in the SYNC gene.
Gastric diseases
Mutations that affect syncoilin or a lack of syncoilin can be contributing factors that lead to cellular necrosis.
The gene SYNC that identifies syncoilin was found to be expressed at higher levels in gastric cancer tissue than in regular gastric tissues. Within the gastric cancer tissues, the syncoilin was found primarily in the cytoplasm and the cell membrane. A recent study shows that gastric cancer tissues that have high SYNC expression reveal a strong correlation with low survival rates for the individual. More specifically, higher gene expression of SYNC in gastric cancer tissues suggests that the individual is at a more advanced stage of gastric cancer and a potentially more aggressive type subtype of
gastric cancer
Stomach cancer, also known as gastric cancer, is a cancer that develops from the lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes, including gastric adenocarcinomas. Lymph ...
.
References
External links
*
{{Muscle tissue